Propadienylindanol

ABSTRACT

5-Cyclohexyl-1-propadienyl-1-indanol and its preparation are described. The compound is useful as an anti-inflammatory.

United States Patent [191 Anderson Apr. 15, 1975 [52] US. Cl.. 260/618 F; 260/247.7 A; 260/293.83; 260/326.87; 260/345.9; 260/347.8; 260/456 R; 260/567.6 M; 260/618 D; 260/618 E;

[51] Int. Cl. C07c 33/06 [58] Field of Search 260/618 F [56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,258,349 6/1973 Germany 260/618 R OTHER PUBLICATIONS Aelin et al., Chem. Abstracts, Vol. 77, 113707U (1972).

Primary Examiner-Joseph E. Evans Assistant ExaminerD. B. Springer Attorney, Agent, or FirmGerald D. Sharkin; Richard E. Vila; Frederick H. Weinfeldt [57] ABSTRACT S-Cyclohexyl-l-propadienyl-l-indanol and its preparation are described. The compound is useful as an antiinflammatory.

1 Claim, No Drawings PROPADIENYLINDANOL This invention relates to an indanol compound, and more particularly, to -cyclohexyl-l-pentadienyl-lindanol, as well as to pharmaceutical compositions containing such compound and to the pharmaceutical use of such compound.

The compound of this invention may be conveniently represented by the formula I:

Compound I is obtainable by reducing with a complex metal hydride, a pentyne compound of the formula ll, (process a):

wherein A is the indanyl residue and Z 2. l l M G) 2 T H IIIa, or '1 H IIIb l 3 Z wherein T is aluminum, gallium or boron, and Z, Z and Z are, independently, a hydrogen atom,

alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms; or alkoxyalkoxy having from 2 to 6 total carbon atoms; Z" and Z are, independently, hydrogen or alkyl of l to 6 carbon atoms; and M is an alkali or alkaline earth metal, such as lithium,

sodium, potassium, calcium or magnesium. Exemplary of such complex hydrides are lithium aluminum hydride, sodium dihydrobis (Z-methoxyethoxy) aluminate, sodium diethyl aluminum dihydride, lithium borohydride, lithium gallium hydride, magnesium aluminum hydride, lithium diisobutyl'methyl aluminum hydride, lithium trimethoxy aluminum hydride, diethyl aluminum hydride and diborane, preferably lithium aluminum hydride or sodium dihydrobis (2- methoxyethoxy) aluminate.

The complex hydrides (llla and lllb) are either known and may be prepared by methods described in the literature or where not known may be prepared by methods analogous to those for preparing the known 5 compounds. Many of the complex hydrides are commercially available.

Process (a) should be carried out in a medium which is not detrimental to the reaction, such as in an aprotic organic solvent, e.g., an ether such as diethyl ether, tetrahydrofuran or dioxane, an aromatic medium, such as benzene, toluene or pyridine or a saturated aliphatic hydrocarbon, such as pentane, hexane or octane. The medium may be a mixture or a single material. The reaction may, for example, be carried out at about -40 to +120C., e.g., at the boiling point of the medium. However, temperatures of from about l0 to +50C. are preferred. While the higher temperatures result in a faster reaction rate, reactions carried out at lower temperatures tend to give purer products. The reaction product (a Compound 1) may be recovered by conventional means, e.g., by carefully adding a small amount of water or aqueous solution, e.g., aqueous ammonium chloride, or sodium hydroxide to the reaction mixture, filtering off the inorganic by-products or hydrolysis products of the hydride ion source, and then separating the Compound 1 product from the organic phase by such means as precipitation, extraction, crystallization, chromatography or liquid-liquid extraction. As will be appreciated by those skilled in the art, it is preferred to exclude moisture from the reaction, e.g., by use of anhydrous solvents and conditions. The reaction may be advantageously carried out in an inert atmosphere, e.g., under nitrogen gas.

The compounds of formula ll in which L is a quaternary ammonium radical are compounds of formula lla:

wherein A is as defined above; and L is the radical:

wherein R and R independently represent alkyl having 1 to 4 carbon atoms; unsubstituted cycloalkyl having 5 to 6 ring carbons, i.e., cyclopentyl or cyclohexyl; or together, with N, represent a heterocyclic ring having 5 to 7 members selected from the group consisting of unsubstituted pyrrolidino, piperidino, homopiperidino, morpholino, and their alkyl substituted derivatives containing from 1 to 3 alkyl groups of l to 4 carbon atoms;

R represents alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl or butyl including isomeric forms where they exist, although the unbranched alkyls are preferred, especially methyl, and

X is an anion derived from a mineral acid or an organic sulfonic acid, provided that X is not fluoro, e.g., iodo or methylsulfonyl.

Compounds iia can be prepared by quaiernizing a compound of the formuia V:

R and R are as defined dove. with a compound of tire formula Vi:

wherein A is as defined above, and L" is tetraizydroluran-Z-yioxy, tetrabydropyrawl vioxv or i-metizox -tetraii= dro ran-4- iox i be prepared by reacting the compound of the for- Mm m:

wherein is defined above, wizh Grignard reagent formed by ireating a compound of the formula i iii:

iii, C-QH -i'." Vlii wherein L" is as defined above, with eil'iyi, magnesium bromide in the conventionai manner for carrying out Grignard reactions.

The compounds of formuiae Vii and Vi'lil used in the production of compounds iib are known or can be prepared from known compounds using conventional techniques.

the compounds of forrnuia il in which i. is inalo other iiiun iodo, i.e., those compounds of formuia iic:

wherein A is as defined above, and L is i'iuoro, cliioro or brorno can be prepared by reacting the compound of the iorrnuia IX:

LII

wlr rein A is as defined above with the appropriate halide seiected from the group of thionvi chloride or bromid-e, phosphorus pentaciiloride or bromide and hydrocarbon sulfonyl fluorides, e.g., enzyi sulfonyi fluoride, iosyi fluoride and mesyi fluoride, in an organic medium such as hexane. benzene or dimeiiioxyglycoi. For the chlorinaiion and bromination a tertiary amine base, such as pyridine. is included in tire reaction mixture and the reaction temperature is ZBbOUiZ i) to 20C. For the i'luorination the reaction temperature is 9 to about C. Compound of formula ii in which is is iodo is conveniently prepared by reacting corresponding compounds of formula iic in which if is cinloro, with sodium iodide in acetone, the reaction being carried out in conventional manner for repiacing a CiiiOIO Wiii'l an iodo.

The compounds of iorrnula ii in which is is a sulfonyloxy radicai are compounds of formula lid:

- cii L I'Id wherein A is as defined above.

i." is a suii'onyloxy radicai which may be either ailiyisulfonyloxy in which the aikyi group may be substiiuted, e.g., haio, or unsubstituted and contain from l to as many as E6 or more. preferably 1 to 6 carbon atoms, e.g., methane suiionyloxy, ethanesulfonyioxy, 3-ciiioropropanesnlfonyloxy. or iiiexadecanesnifonyioxy; or aryisuii'onyloxy in which iiie aryi group is phenyi, napinnyl or substituted phenyl, which may have from i to 3 substituents independen'ziy, seiected from the group consisting of alkyl of 1 2o 5 carbon atoms, aikoxy of l to a carbon atoms, iiaio and nitro.

Compounds iid can prepared by reacting a compound of the formula W. above with an appropriate 21!- lcylsnifonyl ciiioride, such as meii'ianesulfonyi chloride, 3-cnioropropanesulfonyi cnioride or 1- iiexadecanesuli'onyl chioride or an aryisulionyl chlo ride, such as benzensuii'onyi chioride, 4- toinenesnifonyi chloride or Z-napniiiaienesuEfonyi chloride. This reaciion is convenientiy carried out in pyridine at or about room temperature.

The compound of iorrnuia XX used in time production of compounds lie and Kid can be prepared by conven-.

Zionai nydroiysis of a co: pound of formula W0, such as with a mineral or organic acid.

the compounds of formula V used in the preparation of Conipounds iia, above, can be prepared by reacting a compound of formula Jill above with a compound 0? iorrnuia Xi:

Lie c cii wnerein i i and are as defined above. This reaciion may be carried out iernperatures of 0 to 50C, convenieniiy at temperance. and in the presence oi organic soivent such as te lraiiydrofuran.

The compounds of formula Xl are known or can be produced in known manner by reacting a compound of the formula XlJ;

MC: C,ll N I XIV wherein R and R are as defined above, with lithium metal at a temperature of 0 to 50C. in a suitable solvent such as ethylene diamine. The compounds of formula V can also be prepared by a process (b) which involves reacting the compound of formula Xll XII wherein A is as defined above, with a compound of formula Xlll:

no c11 N x111 wherein R and R are as defined above.

in process (b), a compound of formula Xll is reacted with a compound of formula Xlll at a temperature of l0 to 50C. preferably at room temperature, in the presence of an inert solvent, and in the presence of mono-valent coinage metal ion, e.g., copper ion, as catalyst, preferably cuprous chloride or cuprous oxide, although salts and the like of other coinage metals, i.e., silver and gold (i), can likewise be used. The compounds of formula Xll can be prepared by reacting a compound of formula Vll above in a solvent such as dimethylacetamide or dimethyl sulfoxide with a suitable acetylene reagent, such as sodium or lithium acetylide conveniently at room temperature.

The compounds of formulae Xlll and XlV used in the above-identified preparations of compounds V are ltnown or can be produced from known materials by conventional techniques, and many are commercially available.

The compound of formula (I) is useful because it possesses pharmacological activity in animals. in particular, the compound (l) is useful as an antiinfiammatory agent as indicated by the Carrageenan induced edema test on rats (oral administration at l to 200 mg/lrg). For such use, the compound may be combined with a pharmaceutically acceptable carrier, and such other conventionaladiuv'ants as may be necessary, and administered orally in such forms as tablets and capsules, elixirs, suspensions and the like or parenterally in the form of an injectable solution or suspension. The dosage administered will, of course, vary depending upon the condition being treated and the mode of administration. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 milligram to about 250 milligrams per kilogram, e.g., from about 1 milligram to about 75 milligrams:per kilogram of body weight, preferably given in divided doses. 2 to 4 times a day, or in sustained release form. For most'mamrnals, the administration of from about milligrams to about 3,000 milligrams, e.g., from about milligrams to about 2,000 milligrams, of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise from about 25 milligrams to about 1.500 milligrams, e.g., from about 40 milligrams to about 1,000 milligrams, of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

For the above usage, oral administration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for manufacture or pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia. and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques ot delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose. tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preseratives (ethyl-phydroxybenzoate). Capsules preferably contain the active ingredient admixed with an inert diluent, e.g., calcium carbonate, calcium phosphate, kaolin, polyethylene glycol, peanut oil or sesame oil. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly tablets or solid or liquid diluentfilled capsules, as appropriate to the nature of theparticular active ingredient.

Representative formulations for administration, 2 to 4 times a day, in treating inflammation are liquid-filled, soft gelatin capsules prepared by conventional techniques and containing the -llowing:

ingredient Weight in Milligrams S-cyclohexyll -propadicnyll -indanol 50 peanut or sesame oil Example S-cyclohexyll -propadienyll -indanol Step A. To a Grignard mixture prepared in conventional manner from 8.4 g. of magnesium (etched in chloroform and iodine) and 41 g. of ethyl bromide in a total of 200 ml. of dry tetrahydrofuran. there is dropwise added a solution of 47.6 g 3-(2'-tetrahydropyranyloxy)-propyne in 75 ml. of dry tetrahydrofuran. After l.5 hours at room temperature a solution of 2l.43 g 5-cyclohexylindanone in 100 ml. of dry tetrahydrofuran is dropwise added. After remaining for 18 hours at the reaction mixture is poured into 600 ml. of saturated ammonium chloride solution. The aqueous phase is extracted once with 300 ml. of benzene. The combined organic phases are then washed with 500 ml. of IN potassium hydroxide and then 300 ml. of saturated sodium chloride. respectively. dried over anhydrous magnesium sulfate. and evaporated to obtain crude S-cyclohexyl l-(3-tetrahydropyranyloxyl-propyne )-indan- 1 -ol, which is chromatographed over silica gel to obtain a yellow oil.

Step B. In a nitrogen atmosphere. a solution of l 1.4 g. of the product of Step A. in 1 l0 ml. of dry tetrahydrofuran. in an ice bath. there is added. dropwise. 30 ml. of lithium aluminum hydride in ether (1.] molar). The mixture is stirred for 2 hours with ice-bath cooling, and then allowed to stand for 18 hours at 25. 10 ml. of 20 percent aq. potassium hydroxide is then carefully added, followed by 10 g. of sodium sulfate and 2 g. of magnesium sulfate. The mixture is filtered and then evaporated to obtain a crude oil which is purified by chromatographic separation and silica gel preparative plate to give refined 5-cyclohexyl-l-propadienyl-lindanol, as a yellow oil.

What is claimed is:

l. The compound of the formula: 

1. THE COMPOUND OF THE FORMULA: 